Gamma-amino butyric acid (GABA) is considered one of the major inhibitory neurotransmitter in the central nervous system (Sosnowski, M. and T. L. Yaksh, 1990, Spinal administration of receptor-selective drugs as analgesics: New Horizons. J. Pain Symptom. Manage. 5: 204-213). When released, GABA interacts with receptors present on the cell membrane which results in a reduction of neuronal excitability. GABA receptors can be divided in three classes, GABAA, GABAB and GABAC.
GABAA receptors belong to the superfamily of ligand-gated chloride ion channel receptors and constitute the site of action of many drugs. Accordingly, the binding of GABA to its receptor can be modulated by simultaneous binding of different chemical entities to allosteric sites on the ion channel complex. One of these allosteric sites is the benzodiazepine binding site. Ligands of the benzodiazepine binding site on the GABAA receptor complex are either agonists, antagonists or inverse agonists.
Benzodiazepines, widely used for their antidepressant, anxiolytic, sedative, myorelaxant, and anticonvulsant properties, modulate the binding of GABA to GABAA receptors. Benzodiazepines have also been reported in the treatment of chronic pain (Fernandez F. et al., 1987, Analgesic Effect of Alprazolam in Patients With Chronic, Organic Pain of Malignant Origin, J. of Clinical Psychopharmacology, 7:167-169). For example, benzodiazepine agonists increase the binding of GABA to GABAA receptor and promote Cl− influx. Examples of such benzodiazepine agonists include alprazolam (8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4] benzodiazepine), bromazepam, chlordiazepoxide, clonazepam, clorazepate dipotassium, diazepam, estazolam, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, oxazepam, quazepam, temazepam and triazolam.
The long-term high-dose use of benzodiazepines agonists can be problematic due to the decrease in the efficacy of the GABAA receptors leading to the development of tolerance and dependence. The principal side effects of the benzodiazepines are sedation, paradoxal effects, sleepiness, fatigue, weakness, cognitive and/or motor impairment. Moreover, cessation of benzodiazepines may produce withdrawal symptoms with resultant anxiety, insomnia, reduced appetite and weight, perceptual disturbances and tremor.
Several ligands can block the actions of benzodiazepine agonists by competitive inhibition of benzodiazepine receptors. Benzodiazepine antagonists are used, for example, to reverse the adverse pharmacological effects of benzodiazepine agonists, such as their sedative effects, to regenerate the sensitivity response and prevent tolerance of benzodiazepine and for the management of benzodiazepine overdose. Such uses are well known in the art and are described, for example, in U.S. Pat. Nos. 4,595,684, 4,666,903, 4,713,838 and 4,925,844.